Neutralizing monoclonal antibodies elicited by mosaic RBD nanoparticles bind conserved sarbecovirus epitopes

Fan, Chengcheng; Cohen, Alexander A.; Park, Miso; Hung, Alfur Fu-Hsin; Keeffe, Jennifer R.; Gnanapragasam, Priyanthi N. P.; Lee, Yu E.; Gao, Han; Kakutani, Leesa M.; Wu, Ziyan; Kleanthous, Harry; Malecek, Kathryn E.; Williams, John C.; Bjorkman, Pamela J.

doi:10.1016/j.immuni.2022.10.019

Neutralizing monoclonal antibodies elicited by mosaic RBD nanoparticles bind conserved sarbecovirus epitopes

Journal Article · Thu Oct 27 00:00:00 EDT 2022 · Immunity

DOI:https://doi.org/10.1016/j.immuni.2022.10.019· OSTI ID:2006467

Fan, Chengcheng ^[1]; Cohen, Alexander A. ^[2]; Park, Miso ^[3]; Hung, Alfur Fu-Hsin ^[4]; Keeffe, Jennifer R. ^[2]; Gnanapragasam, Priyanthi N. P. ^[2]; Lee, Yu E. ^[5]; Gao, Han ^[2]; Kakutani, Leesa M. ^[2]; Wu, Ziyan ^[2]; Kleanthous, Harry ^[6]; Malecek, Kathryn E. ^[2]; Williams, John C. ^[3]; Bjorkman, Pamela J. ^[2]

California Institute of Technology (CalTech), Pasadena, CA (United States); SLAC
California Institute of Technology (CalTech), Pasadena, CA (United States)
City of Hope, Duarte, CA (United States)
City of Hope, Duarte, CA (United States); Rakuten Medical Inc., San Diego, CA (United States)
California Institute of Technology (CalTech), Pasadena, CA (United States); Stanford Univ., CA (United States)
Bill and Melinda Gates Foundation, Seattle, WA (United States)

Increased immune evasion by SARS-CoV-2 variants of concern highlights the need for new therapeutic neutralizing antibodies. Immunization with nanoparticles co-displaying spike receptor-binding domains (RBDs) from eight sarbecoviruses (mosaic-8 RBD-nanoparticles) efficiently elicits cross-reactive polyclonal antibodies against conserved sarbecovirus RBD epitopes. Here, we identified monoclonal antibodies (mAbs) capable of cross-reactive binding and neutralization of animal sarbecoviruses and SARS-CoV-2 variants by screening single mouse B cells secreting IgGs that bind two or more sarbecovirus RBDs. Single-particle cryo-EM structures of antibody-spike complexes, including a Fab-Omicron complex, mapped neutralizing mAbs to conserved class 1/4 RBD epitopes. Structural analyses revealed neutralization mechanisms, potentials for intra-spike trimer cross-linking by IgGs, and induced changes in trimer upon Fab binding. In addition, we identified a mAb-resembling Bebtelovimab, an EUA-approved human class 3 anti-RBD mAb. These results support using mosaic RBD-nanoparticle vaccination to generate and identify therapeutic pan-sarbecovirus and pan-variant mAbs.

View Accepted Manuscript (DOE)

Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 2006467

Journal Information:: Immunity, Journal Name: Immunity Journal Issue: 12 Vol. 55; ISSN 1074-7613

Publisher:: Cell PressCopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
COVID-19
SARS-CoV-2
X-ray crystallography
coronavirus
cryo-electron microscopy
mosaic nanoparticle
neutralizing antibodies
sarbecovirus
vaccine design

Neutralizing monoclonal antibodies elicited by mosaic RBD nanoparticles bind conserved sarbecovirus epitopes

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